Engineered deletions of HIV replicate conditionally to reduce disease in nonhuman primates

Fathima N Nagoor Pitchai; Elizabeth J Tanner; Neha Khetan; Gustavo Vasen; Clara Levrel; Arjun J Kumar; Shilpi Pandey; Tracy Ordonez; Philip Barnette; David Spencer; Seung-Yong Jung; Joshua Glazier; Cassandra Thompson; Alicia Harvey-Vera; Hye-In Son; Hye-In Son; Steffanie A Strathdee; Leo Holguin; Ryan Urak; John Burnett; William Burgess; Kathleen Busman-Sahay; Jacob D Estes; Ann Hessell; Christine M Fennessey; Brandon F Keele; Nancy L Haigwood; Leor S Weinberger

doi:10.1126/science.adn5866

Engineered deletions of HIV replicate conditionally to reduce disease in nonhuman primates

Science. 2024 Aug 9;385(6709):eadn5866. doi: 10.1126/science.adn5866. Epub 2024 Aug 9.

Authors

Fathima N Nagoor Pitchai^#^{1

2}, Elizabeth J Tanner^#^{1

2}, Neha Khetan^{1

2}, Gustavo Vasen^{1

2}, Clara Levrel^{1

2}, Arjun J Kumar^{1

2

3}, Shilpi Pandey⁴, Tracy Ordonez⁴, Philip Barnette⁴, David Spencer^{4

5}, Seung-Yong Jung¹, Joshua Glazier¹, Cassandra Thompson^{1

6}, Alicia Harvey-Vera, Hye-In Son^{7

8

9}, Hye-In Son¹, Steffanie A Strathdee⁷, Leo Holguin⁷, Ryan Urak¹⁰, John Burnett^{10

11}, William Burgess⁹, Kathleen Busman-Sahay⁹, Jacob D Estes^{9

12

13}, Ann Hessell⁴, Christine M Fennessey¹⁴, Brandon F Keele¹⁴, Nancy L Haigwood⁴, Leor S Weinberger^{1

2

15

16}

Affiliations

¹ Gladstone Center for Cell Circuitry, University of California, San Francisco, CA, USA.
² Gladstone Institute of Virology, University of California, San Francisco, CA, USA.
³ Department of Bioengineering, University of Washington, Seattle, WA, USA.
⁴ Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
⁵ Absci Corporation, Vancouver, WA, USA.
⁶ Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
⁷ Global Health Sciences, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
⁸ US-Mexico Border Health Commission, Tijuana, Mexico.
⁹ Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA.
¹⁰ Center for Gene Therapy, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
¹¹ Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
¹² Faculty of Health, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
¹³ School of Health and Biomedical Sciences College of Science, Engineering and Health RMIT University, Melbourne, Australia.
¹⁴ AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
¹⁵ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
¹⁶ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.

^# Contributed equally.

PMID: 39116226
PMCID: PMC11545966 (available on 2025-08-09)
DOI: 10.1126/science.adn5866

Abstract

Antiviral therapies with reduced frequencies of administration and high barriers to resistance remain a major goal. For HIV, theories have proposed that viral-deletion variants, which conditionally replicate with a basic reproductive ratio [R₀] > 1 (termed "therapeutic interfering particles" or "TIPs"), could parasitize wild-type virus to constitute single-administration, escape-resistant antiviral therapies. We report the engineering of a TIP that, in rhesus macaques, reduces viremia of a highly pathogenic model of HIV by >3log₁₀ following a single intravenous injection. Animal lifespan was significantly extended, TIPs conditionally replicated and were continually detected for >6 months, and sequencing data showed no evidence of viral escape. A single TIP injection also suppressed virus replication in humanized mice and cells from persons living with HIV. These data provide proof of concept for a potential new class of single-administration antiviral therapies.

MeSH terms

Animals
Artificial Virus-Like Particles*
Basic Reproduction Number
Disease Models, Animal
Gene Deletion*
Genetic Engineering
HIV Infections* / therapy
HIV Infections* / virology
HIV-1* / genetics
HIV-1* / physiology
Humans
Macaca mulatta
Mice
Proof of Concept Study
Simian Immunodeficiency Virus / genetics
Simian Immunodeficiency Virus / physiology
Viral Interference*
Viremia / therapy
Viremia / virology
Virus Replication*

Abstract

MeSH terms

Grants and funding